γKlotho is a novel marker and cell survival factor in a subset of triple negative breast cancers

Abstract

Over the last decade, breast cancer mortality has declined. However, triple negative breast cancer (TNBC) remains a challenging problem mostly due to early recurrence and lack of molecularly driven treatments. There is a critical need to identify subgroups of TNBC with common molecular features that can be therapeutically targeted. Here we show that in contrast to Klotho and βKlotho, the third member of the Klotho protein family, γKlotho, is overexpressed in more than 60% of TNBCs and correlates with poorer disease progression. Furthermore, we find that γKlotho is expressed in a subset of TNBC cell lines promoting cell growth. Importantly, we demonstrate that in these cells γKlotho is necessary for cell survival and that its depletion leads to constitutive ERK activation, cell cycle arrest and apoptosis. Interestingly, we observe increased oxidative stress in γKlotho-depleted cells suggesting that γKlotho enables cancer cells to cope with an oxidative environment and that cells become dependent on its expression to maintain this survival advantage. These findings indicate that γKlotho might be a potential marker for patients that would benefit from treatments that alter oxidative stress and constitutes a novel drug target for a subset of TN breast cancers.

Gamma-Klotho exhibits multiple roles in tumor growth of human bladder cancer

“…Trošt et al . showed that, in patients with triple negative breast cancer, the expression level of KLγ was high and correlates with poor progression, that KLγ was a necessary factor for cell survival, and that depletion of KLγ resulted in cell cycle arrest, apoptosis, and persistent activation of the ERK1/2 signaling pathway [ 22 ]. Therefore, we hypothesize that KLγ plays a role in the promotion of bladder cancer and that the balance of existing KLs affects downstream signaling, including that of FGF and FGFR.…”

“…With regard to KLγ, there are fewer reports about the association between KLγ and cancer. Previous reports showed that KLγ has an important role in the cell proliferation ability of colon cancer and the expression level of KLγ was associated with prognosis in triple negative breast cancer [ 21 , 22 ]. In the present study, we focused on the clinical significance of KLγ, which could be a regulator of cancer progression for UCB.…”

γ‑Klotho is correlated with resistance to docetaxel in castration‑resistant prostate cancer

“…To our knowledge, there are only three reports on the association between KLG and cancer development (9,23,24). The present study is the first report of the relationship between KLG and prostate cancer.…”

“…Kim et al reported that KLG is an important factor in cell proliferation by activating ERK1/2 signaling pathway in colon cancer (9). Trošt et al reported that high expression level of KLG correlates with poor disease progression and that in vitro analysis indicated that KLG was a necessary factor for cell survival; depletion of KLG resulted in cell cycle arrest, apoptosis, and persistent activation of the ERK1/2 signaling pathway in patients with triple-negative breast cancer (24). Therefore, we speculate that KLG plays a role in the promotion of prostate cancer growth and that the balance of existing KLs affects activation of various pathways, including FGF/FGFR signaling.…”

“…However, the relationship between KLG and cancer progression remains unclear. Currently, there are very few reports on the association between KLG and cancer (9,23,24). One study reported that KLA enhances the activity of chemotherapeutic drugs on pancreatic cancer cells (25).…”